Project Summary ALS is a devastating and fatal disease. At present there is no treatment that can halt or reverse this disease. Current scientific consensus indicates that this and other neurodegenerative diseases are caused by the accumulation of toxic protein aggregates in the central nervous system. Therefore, clearing these protein aggregates may achieve slowing down, halting or reversing the progression of these diseases. This proposal will test a novel active vaccination strategy in two mouse models for ALS expressing mutant SOD1 and mutant PFN1, respectively. This strategy employs vaccines that are composed of the misfolded pathogenic proteins and rapamycin encapsulated in glucan microparticles. The key advantage of this new strategy over the previously established approaches is its capability in triggering a robust humoral immune response against the mutant protein while containing the detrimental neuroinflammation associated with the immune response against the misfolded proteins. We predict that this vaccine will raise high levels of antibodies against the misfolded and aggregated mutant proteins, clear the protein aggregates and thereby neutralize the mutant proteins' toxicity without triggering neuroinflammation. Ultimately we believe these effects will lead to clinical benefit including slowing down or halting the disease. If these predictions are realized, we will have a new efficacious vaccine candidate to move forward into clinical trial for treatment of ALS.